JP2017125028A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide oral delivery systems that enable controlled and site specific release of drugs such as levodopa and other drugs used in the treatment of Parkinson's disease and other movement disorders, in order to achieve maximal absorption, bioavailability and optimum blood levels.SOLUTION: Provided is an oral pharmaceutical composition comprising coated particles of a complex comprising at least one active agent and an ion exchange resin, where the particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material, as well as a method for producing the oral pharmaceutical composition.SELECTED DRAWING: None

Description

  The present invention relates to oral pharmaceutical compositions that provide controlled site-specific drug release.

(Background of the Invention)
Controlled release of the active drug is an important aspect in the oral administration of any drug. It is particularly important for oral administration of active drugs with a narrow therapeutic window. One example of such an active drug is levodopa, a selective agent in the treatment of Parkinson's disease.

  Parkinson's disease (PD) is one of the most common neurodegenerative diseases, typically occurring in the elderly. Several classes of drugs have been used in the treatment of Parkinson's disease, and their success varies.

  The prevalence of diagnosed PD in the population over 55 years old is about 1.4% and increases with age. Furthermore, Parkinson's disease-like symptoms in the elderly are estimated to occur in 30% of the population over 65 years of age. Although PD is considered a multisystem disease, it is primarily a movement disorder caused by persistent long-term degeneration of dopaminergic nerves in the substantia nigra of the midbrain. PD appears only after about 60-80% of these dopaminergic nerves have been degenerated or after about 90% of striatal dopamine has been lost. Dopamine is produced in the substantia nigra, usually reaches the striatum via the nigrostriatal tract, and is released at the striatum synapse. Dopamine deficiency in the striatum resulting from degeneration of dopaminergic neurons in the substantia nigra is thought to be responsible for PD. However, dopamine itself is not absorbed from the gastrointestinal tract and cannot cross the blood brain barrier.

  Currently, drugs containing levodopa, the natural metabolic dopamine precursor, have provided the most effective treatment for PD. Levodopa can pass from the blood-brain barrier to the basal ganglia where it is decarboxylated by the enzyme aromatic L-amino acid decarboxylase (AADC) to produce dopamine, thereby taking up deficient neurotransmitters. Replace. However, AADC is also present in the intestinal wall, liver, kidney and brain capillaries, and the resulting decarboxylation of levodopa and the formation of levodopa metabolites is associated with many side effects (eg nausea, vomiting). Arrhythmia and postural hypotension). Peripheral levodopa decarboxylation can be largely prevented by further administration of a selective extracerebral decarboxylase inhibitor (eg, carbidopa or benserazide), which itself cannot cross the blood brain barrier. Currently, levodopa combined with carbidopa or benserazide is the treatment of choice when applying levodopa. Solid dosage forms containing a combination of levodopa and carbidopa are known and are used in the treatment of PD and other movement disorders. For example, a rapid release oral tablet containing levodopa and carbidopa together with cellulose, magnesium stearate and starch is marketed under the name Cinemet®. However, even levodopa / carbidopa combination therapy is often accompanied by serious side effects such as dyskinesia and psychiatric disorders.

  Furthermore, currently available formulations are effective for a relatively short period of time and may even be harmful under certain conditions. The use of an immediate release formulation of levodopa leads to a rapid rise in levodopa (initially too high and then soon too low to be effective). Furthermore, only about 5% of the levodopa dose administered in this way reaches the brain.

  The usual side effects of levodopa are orofacial or limb chorea or dystonia in the form of involuntary movements (dyskinesias), which often limits the possible doses. Other side effects of levodopa include orthostatic hypotension, nightmares, hallucinations, and occasionally toxic delirium. Hallucinations and delirium are most common in elderly patients with dementia. The drug cannot restore Parkinsonism in some patients without causing some degree of dyskinesia or other side effects.

  These side effects tended to occur at lower doses as treatment continued, and so-called “wearing-off” and “on-off” phenomena emerged as a major problem in long-term treatment of Parkinson's disease levodopa. After 2-5 years of treatment,> 50% of patients begin to experience fluctuations in response to levodopa. In most of these patients, the effect from each dose is shortened (`` wearing-off '' action), and some patients go back and forth between mobility and immobility (`` on- Off "action). The “on” period is usually associated with high or elevated plasma levodopa concentrations, often accompanied by abnormal involuntary movements (ie, dyskinesia) and uncontrollable hyperactivity. The “off” period is associated with low or decreasing plasma levodopa concentrations and slow acting episodes. The change from the “on” period to the “off” period can occur many times a day. Traditionally, such changes have been addressed by keeping individual doses of levodopa as low as possible and using short dosing intervals every 1-2 hours.

  Several techniques are generally known in formulating oral pharmaceutical compositions to control the release behavior of pharmaceutically active drugs.

  Patent Document 1 discloses an ion-exchange resin (which is pharmaceutically active therein) for providing a drug / resin complex (at least a part of the complex is treated with a solvating agent and provided with a diffusion barrier coating). Long-term sustained release pharmaceutical formulations are described. Patent documents 2 to 5 describe similar preparations using different solvating agents and plasticizers.

  U.S. Patent No. 6,057,031 describes a sustained release antitussive syrup suspension for oral administration containing a mixture of coated and uncoated cation exchange resins loaded with dextromethorphan, where the drug / resin About 30% of the composite is coated with a mixture of ethylcellulose or ethylcellulose latex with a plasticizer and a water dispersible polymer.

  Patent Document 7 is a solid orally administrable pharmaceutical composition for slow, zero-order release of a drug having a water solubility of about 1 / 5-1 / 500 (w / w), A surface conditioning compound having a water solubility of about 1 / 1-1 / 40 (w / w), an erosion control compound having a water solubility of about 1 / 1-1 / 10 (w / w), a surfactant and A pharmaceutical composition containing a combination of surfactants is described.

  Patent Document 8 describes a first layer containing one or more drugs that are immediate-release or sustained-release formulations, one or more drugs that are sustained-release formulations (equivalent to those of the first layer or A pharmaceutical tablet comprising a second layer comprising a different) and a low-permeability barrier-type layer covering the second layer or located between the first and second layers It is described.

  Efforts have also been made to provide sustained release, oral, levodopa and carbidopa dosage combinations.

  U.S. Patent Nos. 6,099,028 and 11 describe matrix or monolayer drug delivery systems comprising carbidopa and levodopa as active drugs, wherein the drug is in one of the polymer vehicles. It is uniformly dispersed at a concentration higher than the drug solubility in A preferred vehicle is a combination of hydroxypropyl cellulose, a water soluble polymer, and polyvinylacetate-crotonic acid, a low water soluble copolymer. Another preferred vehicle is polymethyl methacrylate.

  US Pat. No. 6,057,031 relates to a pharmaceutical dosage form for the treatment of a disorder associated with a decrease in dopamine levels in a patient's brain tissue containing both immediate release and sustained release components, including a combination of carbidopa and levodopa. It is described.

  Patent Document 13 describes a pharmaceutical composition containing levodopa, carbidopa and entacapone, especially a pharmacologically effective amount of levodopa, carbidopa and entacapone (wherein a sufficient amount of carbidopa is separated from entacapone and / or levodopa). Oral solid compositions containing

  U.S. Patent No. 6,057,031 discloses a disintegrating layer, an erodible layer and a swellable layer, two of which are outside and one in the middle, each layer containing one or more drugs (eg, levodopa and / or carbidopa) ) Containing a controlled release monolayer system for oral administration.

  A sustained release solid oral dosage form containing levodopa and carbidopa in the polymer vehicles hydroxypropyl cellulose and polyvinyl acetate crotonic acid polymer is marketed under the name Cinemet® CR.

  Current sustained release formulations containing levodopa / carbidopa suffer from a number of disadvantages. In particular, these formulations are typically slow to develop. For example, the peak effect of commercially available Cinemet® CR tablets has been shown to occur 1 hour after the peak effect of conventional Cinemet® tablets. Furthermore, the bioavailability of current sustained release formulations is low. At the same time, the clinical response to sustained release tablets was found to be less reliable and less predictable than conventional formulations. Current sustained release formulations of levodopa suffer from insufficient intra- and inter-patient blood concentration reproducibility. This is a problem, especially in the case of levodopa, and often doses must be gradually increased over time to maintain efficacy, which in turn contributes to the occurrence of long-term side effects.

  In particular, it has been found that current sustained release formulations of levodopa cannot provide as good an effect as continuous administration of levodopa (eg, by intravenous infusion). On the other hand, it has been found that intravenous infusion of levodopa often causes hardening of the peripheral veins in addition to being inconvenient for the patient.

  U.S. Patent No. 6,057,049 describes sustained duodenal pump and enteral administration of levodopa, and optionally a composition containing carbidopa, over a period of 16 hours or more. The obvious disadvantage of this method of levodopa / carbidopa drug delivery is that the patient always needs to be intubated into the duodenum or jejunum (which is cumbersome, painful and prone to infection).

US 4,221,778 US 4,847,077 US 4,859,461 US 4,859,462 US 4,959,219 US 6,001,392 US 4,361,545 WO 94 / 06416A1 US 4,832,957 US 4,900,755 US 4,983,400 US 2003/0224045 A1 WO 01/01984 A1 WO 99/17745 A1 US 2008/0051459 A1

  Accordingly, the object of the present invention is to overcome the disadvantages of the prior art and to achieve a drug (especially a narrow therapeutic window) to achieve maximum absorption, bioavailability and optimal blood concentration. It is to provide an oral delivery system that allows controlled site-specific release of drugs (eg, other drugs used in the treatment of levodopa and Parkinson's disease and other movement disorders).

(Description of the present invention)
In one aspect, the present invention is an oral pharmaceutical composition comprising coated particles of a complex of at least one active drug and an ion exchange resin, wherein the particles comprise at least one bioadhesive substance. The present invention relates to a pharmaceutical composition coated with an adhesive coating layer.

FIG. 1 shows the release of levodopa from the 500 mg levodopa drug resin complex obtained in Example 1A dispersed in deionized water at room temperature under stirring with a magnetic stirrer. NaCl was added as follows: 9 min: 200 mg; 36 min: 700 mg; 52 min: 1200 mg; 61 min: 3300 mg. FIG. 2 shows the dissolution profile of the coated LDRC obtained in Example 1B-1 in phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., pH 5.5, ionic strength 0.075). FIG. 3 shows the dissolution profile of the coated LDRC obtained in Example 1B-3 in a phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., pH 5.5, ionic strength 0.075). Fig. 4 shows the dissolution profile of the coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C, pH 6.0, ionic strength 0.075). FIG. 5 shows the dissolution profile of the coated LDRC obtained in Example 1C-3 in a phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., pH 6.0, ionic strength 0.075). FIG. 6 shows the dissolution profile of the coated LDRC obtained in Example 1C-5 in a phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., pH 6.0, ionic strength 0.075). FIG. 7 shows the dissolution profile of the coated LDRC obtained in Examples 1D-2 to 1D-4 in a phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., dissolution medium 0 to 1 Time: 0.1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ionic strength 0.075). FIG. 8 shows the dissolution profile of the coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., dissolution medium 0-1 Time: 0.1 N HCl, 1-12 hours: phosphate buffer pH 6.25, ionic strength 0.075). FIG. 9 shows the dissolution profiles of uncoated ropinirole drug resin complex (RoDRC) obtained in Example 2A and coated RoDRC obtained in Example 2D before and after sieving (USP Method # 2, Paddle rotation speed 75 rpm, 37 ° C, dissolution medium 0 to 1 hour: 500 ml 0.1 N HCl, 1 to 10 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075) . FIG. 10 shows the dissolution profile of the coated alendronate drug resin complex (AlDRC) obtained in Example 3D (USP method # 2, paddle rotation speed 75 rpm, 37 ° C., dissolution medium 1000 ml 0.1 M NaCl). . FIG. 11 shows the dissolution profile of the coated risperidone drug resin complex (RiDRC) obtained in Example 4D (USP method # 2, paddle rotation speed 75 rpm, 37 ° C., dissolution medium 0 to 1 hour: 500 ml 0.1 N HCl, 1-12 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075). FIG. 12 shows the dissolution profile of the coated olanzapine drug resin complex (OzDRC) obtained in Example 5D (USP method # 2, paddle rotation speed 75 rpm, 37 ° C., dissolution medium 0 to 1 hour: 500 ml 0.1 N HCl, 1-12 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075; 10.5 hours later 10 g NaCl was added).

  The composition according to the invention contains at least one active drug. It will be understood that any such active drug is present in the composition in a therapeutically effective amount. The term “therapeutically effective amount” refers to the total amount or content of active drug that is sufficient to produce a clearly discernable biological response when administered to a patient.

  In general, all pharmacologically active drugs are suitable for use in the compositions of the present invention. Preferred classes of active drugs include antiparkinsonian drugs, antiepileptic drugs, antipsychotics, antidepressants, narcotics, antihypertensives, antioxidants, anti-neoplastic agents, cell growth inhibitors, gastrointestinal drugs and musculoskeletals Examples thereof include musculoskeletal drugs.

  Examples of suitable active drugs include ondansetron, granisetron, tropisetron, dolasetron, palonosetron, aprepitant, sulfasalazine, doxazosin, atenolol, bisoprolol, hydrochlorothiazide, carvedilol, amlodipine, felodipine, nifedipine, verapamil, diltiazem, enalapril, Ramipril, quinapril, cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, fenofibrate, cholestyramine, oxybutynin, propiverine, solifenacin, trospium, cilifenacin, trospium, darifenacin Syn, finasteride, cyclophosphamide, chlorambucil, melphalan, busulfan, lomustine, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, capecitabine, vinblastine, vincristine, vincristine, vincristine, vincristo , Docetaxel, actinomycin D, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, cisplatin, carboplatin, oxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, sunitinib Temsirolimus, Musacrine, asparaginase, hydroxyurea, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, megestrol, tamoxifen, flutamide, nilutamide, bicalutamide, anastrozole, letrozole, exemestane, mycophenolic acid Mofetyl, sirolimus, everolimus, cyclosporine, tacrolimus, azathioprine, etidronate (e.g. sodium etidronate), clodronate (e.g. sodium clodronate), pamidronate (e.g. sodium pamidronate), alendronate (e.g. alendronate) Acid sodium), tiludronic acid (for example, sodium tiludronate), ibandronic acid (for example, sodium ibandronate), risedron (E.g. risedronate sodium), zoledronic acid (e.g. sodium zoledronic acid), morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprenorphine, tramadol, acetylsalicylic acid, methamizole, paracetamol, sumatriptan, methylphenobarbital, phenobarbital , Primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, thiagabin, sultiam, phenacemide, lamotrigine, ferbamate, topiramate, gabapentin, phenetride, levetiracetam, penizoramide, penisamide Bechramid, trihexyphenidyl, biperidene, levo Pa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocryptin, ropinirole, pramipexole, cabergoline, apomorphine, piribezil, rotigotine, selegiline, rasagiline, tolcapone, entacapone, bulomapine, levoprodin Perazine, haloperidol, sertindol, ziprazidone, zuclopentixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium (eg, lithium carbonate), protipendil, risperidone, clothiapine, mosapramine, zotepine, aripiprazole , Paliperidone, diazepam, alprazolam, meprobamate Flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaprocrate, fluvoxamine, etoperidone, escitalopram, mirtazapine, venlafaxine, sulfadip , Methadone, riluzole, abacavir, acyclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonobin, ethambutol, glucose, imipramine, ketorolac, ketorolac, ketorolac , Levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorphan, hydrocodone, hydralazine, metaproterol And propanolamine and pseudoephedrine.

  The compositions of the present invention are particularly suitable for active drugs belonging to class I of the Biopharmaceutical Classification System (BCS). BCS class I active drugs are characterized by both high permeability and high solubility. Examples of BCS class I active drugs include abacavir, acyclovir, amitriptyline, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, cyclophosphamide, desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxepin, doxycycline, Enalapril, ephedrine, ergovinine, ethambutol, fluoxetine, glucose, imipramine, ketorolac, ketoprofen, labetalol, levodopa, levofloxacin, metoprolol, metronidazole, midazolam, minocycline, misoprostol, nifedipine, paracetamolzone fetizolone , Primaquine, promazine, prop Lanolol, quinidine, risperidone, rosiglitazone, salicylic acid, theophylline, verapamil and zidovudine.

  Also preferred are active drugs with a short biological half-life of up to about 8 hours. Examples include codeine, dextromethorphan, doxepin, ephedrine, hydrocodone, hydralazine, metaproterenol, morphine, levodopa, carbidopa, benserazide, entacapone, phenylpropanolamine, pseudoephedrine and verapamil.

  Particularly preferred are levodopa, carbidopa, benserazide, entacapone and mixtures thereof.

  The composition of the present invention may comprise a combination of two or more active drugs. Preferred combinations of active drugs include bisoprolol / hydrochlorothiazide, verapamil / trandolapril, amlodipine / atorvastatin, tramadol / paracetamol, bechramid / trihexyphenidyl, buprenorphine / naloxone, levodopa / carbidopa, levodopa / benserazopide and levodopa / carbidopa / Is mentioned.

  Unless otherwise indicated, all references to active drugs herein are meant to include pharmaceutically acceptable salts and solvates thereof. Such a reference is further meant to encompass both crystalline and amorphous forms. As used herein, the term “pharmaceutically acceptable” refers to a substance suitable for use in humans and animals, without excessive toxicity, commensurate with a reasonable benefit / risk ratio.

  The composition of the present invention contains coated particles of a complex of at least one active drug and an ion exchange resin.

  Suitable ion exchange resins are typically water insoluble and are pharmacologically inert, including covalently bound functional groups (ionic or capable of being ionized under appropriate pH conditions). Contains an organic or inorganic matrix. Examples of organic matrices include synthetic matrices (eg, polymers or copolymers of acrylic acid, methacrylic acid, styrene sulfonate or divinyl benzene sulfonate) and partially synthetic matrices (eg, modified cellulose or dextran). Examples of inorganic matrices include silica gel modified by adding ionic groups. The covalently bonded ionic group can be a strongly acidic group (e.g., a sulfonic acid group), a weakly acidic group (e.g., a carboxylic acid group), a strong basic group (e.g., a quaternary ammonium group), or a weak base. It can be a functional group (eg, a primary amine group) or a combination of an acidic group and a strongly basic group. Ion exchange resins suitable for ion exchange chromatography or water deionization are usually also suitable for use in the present invention. For example, the ion exchange resin is described in HF Walton, “Principles of Ion Exchange” in E. Heftmann (Ed.), “Chromatography: A laboratory handbook of chromatographic and electrophoretic methods”, 3rd ed., Van Nostrand, New York, 1975. , pp. 312-343. Suitable ion exchange resins typically have an exchange capacity of dry resin (free acid or base form) of about 6 meq./g or less, especially about 5.5 meq./g or less. .

  The ion exchange resin is preferably a polymer and copolymer of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups Selected from the group consisting of Suitable ionic groups include sulfonate groups, tertiary amine groups and quaternary ammonium groups. Particularly preferred are polymers and copolymers of styrene sulfonate, styrylmethyltrimethylammonium salt and dimethylaminomethylstyrene.

  More preferably, the ion exchange resin is crosslinked using a crosslinking agent. Suitable crosslinkers are generally known in the art. Preferred crosslinking agents are divinyl and polyvinyl compounds, most preferably divinylbenzene. Preferably, the ion exchange resin is about 3 to about 20%, especially about 4 to about 16%, more preferably about 6 to about 10%, based on the total weight of the dry resin (free acid or base form). Cross-linked to a weight percent and most preferably in the range of about 8 weight percent.

Particularly preferably, the ion exchange resin is a cross-linked sulfonated copolymer of styrene and divinylbenzene, which is preferably cross-linked to a range of about 8% by weight, based on the total weight of the dry resin (H ⁺ -form). . This ion exchange resin typically has an ion exchange capacity of about 4.5 to 5.5 meq./g of the dry resin (H ⁺ -form). Another preferred ion exchange resin is a crosslinked copolymer of styrene (functionalized with quaternary ammonium groups) and divinylbenzene, which is preferably about 8 based on the total weight of the dry resin (H ⁺ -form). Cross-linked to the weight percent range. This ion exchange resin typically has an ion exchange capacity of about 3-4 meq./g of the dry resin (H ⁺ -form).

  The ion exchange resin preferably has an average particle size in the range of about 10 to about 1000 μm, especially in the range of about 20 to about 250 μm, most preferably in the range of 25 to about 200 μm. The ion exchange resin is in the form of irregularly shaped particles having an average particle size ranging from about 40 to about 250 μm, or spherical particles having an average particle size ranging from about 45 to about 150 μm. obtain.

  More preferably, the complex of at least one active drug and an ion exchange resin is about 5-80% by weight, especially 10-70% by weight, more preferably 20-60% by weight, based on the total weight of the complex. %, And most preferably contains 30-50% by weight of active drug.

  The average particle size of the complex of at least one active drug and ion exchange resin is preferably about 10 to 3000 μm, especially about 30 to 2000 μm, and most preferably about 50 to 1000 μm. More preferably, at least about 85%, especially at least about 95%, and most preferably at least about 98% of the particles by weight have an average particle size within these preferred ranges. As used herein, the term average particle size refers to volume average. The particle size can be determined by sieving analysis or laser diffraction analysis generally known in the art. Sieving analysis is typically performed on a dry powder sample. Laser diffraction analysis can be performed using a dry powder sample or a suspension sample in an inert liquid vehicle (eg, purified water), eg, using a Malvern Mastersizer MS 2000.

  The coated particles further contain a bioadhesive coating layer containing at least one bioadhesive substance. The term “bioadhesive” generally refers to a substance that can provide particles with adhesion to biological surfaces (eg, tissues and / or cells) (especially mucosa).

  Suitable bioadhesive materials generally include modified and unmodified, natural or synthetic, hydrophilic homopolymers, copolymers, and hydrogels. Examples include polycarboxylates, hyaluronan, chitosan, alginate (eg sodium alginate), pectin, xanthan gum, poloxamer, cellulose derivatives, polyvinyl acetate and polyvinylpyrrolidone. Modified and unmodified synthetic polycarboxylate polymers are preferred, which are typically at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most Preferably it has a weight that is an average molecular weight of about 1,000,000 to about 10,000,000 daltons. Modifications can include cross-linking, neutralization, hydrolysis, and complete or partial esterification.

Preferably, the bioadhesive material comprises optionally cross-linked polymers and copolymers of acrylic acid or alkyl acrylic acid, especially copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. Suitable cross-linking agents include polyhydric alcohol vinyls and allyl ethers, especially allyl sucrose, allyl pentaerythritol and divinyl glycol. Particularly preferred are homopolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol and copolymers of acrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl crosslinked with allyl pentaerythritol.

  More preferably, the bioadhesive coating layer is 1 to 30% by weight, especially 2 to 10% by weight, based on the combined weight of the composite, the optionally present release modifying coating layer, and the bioadhesive coating layer. And more preferably in an amount of 3-7% by weight.

  The coated particles optionally include a modified release coating layer (located between the composite and the bioadhesive layer and containing at least one release modifying substance). In certain embodiments, particularly when the active drug belongs to Biopharmaceutical Classification System (BCS) Class II or IV (characterized by the active drug exhibiting low solubility), the composition comprises: It consists only of particles that do not contain a modified release coating layer. Preferably, at least some of the coated particles comprise a release modifying coating layer. The release modifying substance is preferably selected from delayed release substances and / or sustained release substances.

  Suitable delayed release materials are typically not soluble or erodible in the first environment or limited while being soluble in the second environment and / Or erosive. Examples of suitable delayed release materials include anionic cellulose derivatives, anionic vinyl resins, anionic acrylic resins, and combinations thereof. Preferred anionic cellulose derivatives include cellulose ethers, cellulose esters and cellulose ester-ethers, especially alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses and acylcelluloses, which are esterified with di- or tricarboxylic acids. ing. Particularly preferred are cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose succinate. Preferred anionic vinyl resins include polyvinyl esters esterified with di- or tricarboxylic acids. Polyvinyl acetate phthalate is particularly preferred. Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkyl acrylic acid, especially copolymers of acrylic acid or methacrylic acid and alkyl acrylate or alkyl methacrylate. Poly (methacrylic acid-co-ethyl acrylate) and poly (methacrylic acid-co-methyl methacrylate) are particularly preferred. Cellulose acetate phthalate, polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate) 1: 1, hydroxypropylmethylcellulose succinate acetate, poly (methacrylic acid-co-methyl methacrylate) 1: 1, poly (methacrylic acid) Acid-co-methyl methacrylate) 1: 2 and combinations thereof are most preferred as delayed release materials, cellulose acetate phthalate, polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate) 1: 1, succinate Most preferred are hydroxypropylmethylcellulose acid and combinations thereof.

  Suitable sustained release materials generally include natural and synthetic film forming materials having diffusion barrier properties. Such materials are generally insoluble in water and should be permeable to water and the active drug. However, it may desirably include a water soluble material (eg, methylcellulose) to alter the permeability of the coating, or may include an acid insoluble and base soluble material to act as an enteric coating. Examples of suitable sustained release materials are also described in R. C. Rowe in “Materials used in Pharmaceutical Formulation”, A. T. Florence (Ed.), Blackwell Scientific Publications, Oxford, 1984, pp. 1-36. Examples of suitable sustained release materials include cellulose derivatives (eg, cellulose ethers and cellulose esters), (meth) acrylic resins (eg, acrylate and methacrylate polymers and copolymers), vinyl resins (eg, vinyl pyrrolidone, vinyl acetate). And vinyl chloride polymers and copolymers), shellac, zein, rosin esters, silicone elastomers and mixtures thereof. Preferred cellulose derivatives include alkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose and acylcellulose, especially ethylcellulose, methylcellulose, hydroxypropylmethylcellulose and cellulose acetate. Preferred (meth) acrylic resins include acrylate and methacrylate copolymers containing quaternary amine functional groups as appropriate, especially poly (ethyl acrylate-co-methyl methacrylate) and poly (ethyl acrylate-co-methyl methacrylate). -Co-trimethylammonioethyl methacrylate chloride), more particularly poly (ethyl acrylate-co-methyl methacrylate) 2: 1, poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) ) 1: 2: 0.1, and poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1: 2: 0.2. Preferred vinyl resins include polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate) and mixtures thereof. Ethyl cellulose, methyl cellulose and mixtures thereof are particularly preferred. Most preferably, the sustained release coating contains a water-based ethylcellulose latex or pseudolatex plasticized with dibutyl sebacate or vegetable oil.

  The modified release coating layer is preferably about 5 to about 70% by weight, especially about 10 to about 60% by weight, and more preferably about 20 to about 50% by weight, based on the combined weight of the composite and the modified release coating layer. % Present. By varying the amount of release modifying material and / or using a mixture of coated and uncoated particles, the dissolution profile can be selectively modified as desired. It is preferred that about 20 to about 80%, more preferably about 30 to about 70%, and most preferably about 40 to about 60% of the particles comprise a modified release coating layer.

  According to a preferred embodiment, the composition contains at least two groups of coated particles that differ in amount and / or composition of the release-modifying substance and / or contain different active drugs.

  In one embodiment, the composition comprises a first group of coated particles comprising a modified release layer, and a second group of coated particles comprising a modified release layer that does not comprise a modified release layer or contains a small amount of a modified release material. Containing. In another embodiment, the composition contains two groups of coated particles comprising release modifying layers that differ in the composition of the release modifying material. In these embodiments, particles that include a modified release layer that does not include a modified release layer or that includes a small amount of a modified release material will exhibit faster release of the active drug. Similarly, groups of particles with different compositions of release modifying substances will exhibit different release behaviors.

  If the composition contains at least two different groups of coated particles, the active drugs of these groups of particles can be the same or different. If the active drugs are the same, different groups of coated particle combinations exhibiting different release behaviors can be used to accommodate the general release characteristics of the active drug. If the active drugs are different, the different active drugs can be provided according to the different release characteristics (eg, one active drug can be released faster and / or earlier than another active drug).

  Of course, these and other embodiments can also be combined to provide a composition containing any different groups of coated particles. For example, the composition according to the invention comprises a first group of coated particles containing a first active drug or active drug combination comprising a modified release layer, the same active drug or active drug combination not comprising a modified release layer As well as a third group of coated particles containing different active drugs or combinations of active drugs.

  The coated particles optionally include an enteric coating layer that is positioned to cover the bioadhesive layer and contains at least one enteric coating material. The enteric coating layer is preferably positioned to directly cover the bioadhesive layer (ie, there is no separate layer between the bioadhesive layer and the enteric coating layer). Suitable enteric coating materials are generally known in the art. They typically substantially prevent release of the active drug in the stomach by being substantially resistant to gastric juice and promote intestinal release. Examples of suitable enteric coating materials include anionic cellulose derivatives, anionic vinyl resins, and anionic acrylic resins.

  Preferred anionic cellulose derivatives include cellulose ethers, cellulose esters and cellulose ester-ethers such as alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkyl-celluloses or acylcelluloses, which are di- or tricarboxylic acids (e.g. Phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid, and pharmaceutically acceptable salts thereof). Cellulose ether phthalate, cellulose ester phthalate, cellulose ester-ether phthalate and pharmaceutically acceptable salts thereof are preferred. Cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methyl phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose hexahydrophthalate, and the like Particularly preferred are pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts include alkali salts, alkaline earth salts and ammonium salts, especially sodium cellulose acetate phthalate, cellulose calcium acetate phthalate and ammonium hydroxypropylmethylcellulose ammonium phthalate.

  Preferred anionic vinyl resins include polyvinyl esters, which are di- or tricarboxylic acids such as phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid, and pharmaceutically acceptable salts thereof. Esterified. Polyvinyl acetate phthalate is particularly preferred. Even more preferred are mixtures of anionic vinyl resins and phthalate plasticizers (eg, dialkyl phthalates (eg, diethyl phthalate or dibutyl phthalate), alkylaryl phthalates or diaryl phthalates).

  Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkyl acrylic acid, especially copolymers of acrylic acid or methacrylic acid and alkyl acrylate or alkyl methacrylate. Examples include poly (methacrylic acid-co-ethyl acrylate), poly (methacrylic acid-co-methyl methacrylate) and combinations thereof, preferably poly (methacrylic acid-co-methyl methacrylate) 50:50, Poly (methacrylic acid-co-methyl methacrylate) 30:70, poly (methacrylic acid-co-dimethylaminoethyl methacrylate-co-ethyl acrylate), poly (methacrylic acid-co-methyl methacrylate-co-ethyl acrylate), And combinations thereof, more preferably poly (methacrylic acid-co-methyl methacrylate) 50:50 having an average molecular weight of about 135,000 g / mol, poly (methacrylic acid-copolymer) having an average molecular weight of about 135,000 g / mol. -Methyl methacrylate) 30:70, poly (methacrylic acid-co-dimethylaminoethyl methacrylate-co-ethyl acrylate) with an average molecular weight of about 750,000 g / mol, average molecular weight of about 1,000 Poly (methacrylic acid-co-methyl methacrylate-co-ethyl acrylate) that is 0,000 g / mol, and combinations thereof.

  Other suitable enteric coating materials include: (a) keratin, keratin sandalac-tolu, zarol (phenyl salicylate), zarol β-naphthylbenzoate and acetotannin, zarol containing peru balsam, Tolu-containing zarol, gum mastic-containing zarol, zarol and stearic acid, and zarol and shellac; (b) formalized protein, certain forms of gelatin, and certain forms Cross-linked gelatin and ion exchange resins; (c) myristic acid-hardened castor oil-cholesterol, stearic acid-amallow, stearic acid-truvalsum, and stearic acid-castor oil; (d) shellac, ammoniated shellac, ammoniated shellac -Zaroll, shellac-wool fat, shera Mastics containing cetyl alcohol, shellac-stearic acid-truvalsum, and shellac n-butyl stearate; (e) abietic acid, methyl abictate, benzoin, trough balsam, sandalac, trubal sum ), And cetyl alcohol-containing mastics.

  The presence and nature of the enteric coating can be selected depending on the intended release site of the active drug. If the active drug is released in the stomach, the particles will usually not contain an enteric coating layer.

  When the active drug is released in the duodenum, the enteric coating material is preferably selected to dissolve at a pH in the range of about 5.0 to 6.0, especially about 5.5 to 6.0. Particles containing such enteric coatings are particularly preferred when the active drug is levodopa. Suitable enteric coating materials include poly (methacrylic acid-co-ethyl acrylate), especially poly (methacrylic acid-co-ethyl acrylate) 1: 1.

  When the active drug is released in the ileum, the enteric coating material is preferably selected to dissolve at a pH in the range of about 6.0 to 7.0, especially about 6.0 to 6.5. Suitable enteric coating materials include poly (methacrylic acid-co-methyl methacrylate), especially poly (methacrylic acid-co-methyl methacrylate) 1: 1.

  When the active drug is released in the colon, the enteric coating material is preferably selected to dissolve at a pH in the range of about 6.5 to 7.5, especially 7.0 or higher. Suitable enteric coating materials include poly (methacrylic acid-co-methyl methacrylate) and poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), especially poly (methacrylic acid-co-methacrylic acid). Methyl) 1: 2 and poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7: 3: 1.

  It is further preferred that the enteric coating layer is present in an amount of 1 to 80% by weight, especially 10 to 60% by weight and more preferably 30 to 50% by weight, based on the total weight of the coated particles.

  Surprisingly, the oral pharmaceutical composition according to the present invention provides a reproducible, site-specific and sustained release of active drug, thereby releasing the active drug early and quickly. It has been found that the effect develops rapidly and then provides blood levels within the therapeutic area slowly and substantially continuously over an extended period of time (eg, over 1-10 hours). These superior properties reduce the total daily dose required as well as the number of daily doses, thereby reducing both short-term and long-term side effects.

  While not wishing to be bound by any particular theory, the bioadhesive material is intended to retain a large number of coated particles at the desired absorption site of the active drug in the patient's gastrointestinal tract by its adherence to the biological surface. It is considered to be provided. The release rate of the active drug from the complex of ion exchange resin and active drug depends, inter alia, on the ionic strength of the surrounding body fluid at the specific absorption site, which is relatively constant within and between patients. In that way, for example, uncontrolled and irregular release of active drug throughout the digestive tract of the patient is prevented.

  The composition is preferably an active drug characterized in that the total amount of active drug released is less than 60% by weight after 2 hours, less than 70% by weight after 4 hours, and less than 90% by weight after 8 hours. Indicates release (USP method # 2, paddle speed 50 rpm, 37 ° C, dissolution medium 0-1 hour: 500 ml 0.1 N HCl, 1-12 hour: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer ], pH 6.25, ionic strength 0.075).

  It is particularly preferred that the composition exhibits zero order, pseudo zero order, first order or pseudo first order release characteristics. The “zero order” release profile characterizes the release profile of a dosage form that releases a certain amount of drug per unit time. The “pseudo-zero order” emission characteristic approximates the zero order emission characteristic. The “primary” release profile characterizes the release profile of a dosage form that releases a certain percentage of the initial drug charge per unit time. A “pseudo-first order” emission characteristic approximates the primary emission characteristic.

  The average particle size of the coated particles is preferably about 20 to about 5000 μm, especially about 50 to about 4000 μm, and most preferably about 70 to about 3000 μm. It is further preferred that at least about 85%, especially at least about 95%, and most preferably at least about 98% of the volume of the particles have an average particle size within these preferred ranges.

The coated particles typically have a specific gravity (SG) higher than the specific gravity of duodenal juice (SG = 1.008-1.03) or the specific gravity of intestinal fluid (SG = 1.007-1.009). As used herein, the term “specific gravity” means the ratio of the density of particles to the density of water at 4 ° C. Preferably, the coated particles have a specific gravity in the range of 1.1 to 2.0, more preferably in the range of 1.2 to 1.8. The specific gravity of the coated particles can be calculated from the volume of water displacement (ΔV) obtained by adding the sample to water at 4 ° C. according to the following formula (sample mass (m) and water density at 4 ° C. ( ρH ₂ O)): SG = (m / ΔV) / ρH ₂ O.

The coated particles according to the present invention typically exhibit a large specific surface area. As used herein, the term “specific surface area” typically means BET surface area. The BET surface area was calculated from nitrogen desorption data obtained on a BET FlowSorb II 2300 (Micromeritics Instrument Corp., USA) using a mixture of 30% by volume nitrogen and 70% by volume helium at 77 K. Can be determined. Preferably, the coated particles exhibit a specific surface area in the range of about 3,000 to 20,000 m ² / m ³ . In another embodiment, the coated particles exhibit a specific surface area in the range of about 1 to 200 m ² / g.

  In one embodiment, an oral pharmaceutical composition according to the present invention comprises coated particles of a complex of at least one active drug and an ion exchange resin, wherein (i) the particles contain at least one bioadhesive substance. And (ii) the coated particles are further positioned so as to cover (preferably directly cover) the bioadhesive layer and at least one enteric coating An enteric coating layer containing the substance is included.

  In another embodiment, the oral pharmaceutical composition according to the invention contains coated particles of a complex of at least one active drug and an ion exchange resin, wherein (i) the particles are at least one bioadhesive And (ii) at least a portion of the coated particles is further positioned between the composite and the bioadhesive layer to provide at least one release. A release modifying coating layer containing the modifying material is included.

  According to a preferred embodiment, the oral pharmaceutical composition according to the invention contains coated particles of a complex of at least one active drug and an ion exchange resin, wherein (i) the particles are at least one bioadhesive. (Ii) the coated particles are further positioned to cover the bioadhesive layer and contain at least one enteric coating substance. And (iii) at least a portion of the coated particle further comprises a release modifying coating layer located between the composite and the bioadhesive layer and containing at least one release modifying material.

According to a particularly preferred embodiment, the coated particles are based on the total weight of the coated particles:
(a) 1-50% by weight, especially 5-40% by weight, preferably 10-20% by weight of at least one active drug;
(b) 1-50% by weight, especially 10-35% by weight, preferably 15-25% by weight of ion exchange resin;
(c) 0-50% by weight, especially 1-50% by weight, preferably 10-40% by weight, more preferably 15-30% by weight of the release-modifying substance;
(d) 0.5-30% by weight of bioadhesive material, especially 1-10% by weight, preferably 2-8% by weight; and
(e) 0-80 wt% enteric coating material, especially 1-80 wt%, preferably 10-60 wt%, more preferably 30-50 wt%;
Containing.

  The composition may further contain at least one active drug or a pharmaceutically acceptable salt or solvate thereof on the outside of the coated particles to provide a rapid rise in active drug. The active drug can be the same as or different from the active drug contained in the coated particles. The active drug can optionally be coated with an enteric material.

  The composition according to the invention is particularly suitable for active drugs with a narrow therapeutic window (for example levodopa, carbidopa, benserazide and / or entacapone).

  In an especially preferred embodiment, the composition contains levodopa and carbidopa or benserazide in the range of 20: 1 to 1: 1, preferably 15: 1 to 2: 1, most preferably 10: 1 to 4: 1. .

  In the final formulation, other suitable materials can be mixed in addition to the various forms of coated particles described above. These other materials can be bound to the ion exchange resin and optionally coated with some or all of the above coating layers to provide the desired dissolution profile, or they can be released free. It can be in a free native solid form or a liquid form.

  The composition of the present invention may further contain an excipient. Suitable types of excipients include adsorbents, antioxidants, acidifying agents, alkalizing agents, buffering agents, coloring agents, flavorants, sweeteners, antiadherents, binders, Diluents, direct-acting excipients, disintegrants, glidants, lubricants, opacifiers and / or polishing agents.

  The term “antioxidant” generally refers to an excipient that is used to prevent alteration of the active drug by the oxidation process by inhibiting oxidation. Suitable antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, formaldehyde sulfoxylic acid Sodium and sodium metabisulfite are mentioned.

  The term “sweetening agent” generally refers to an excipient used to sweeten a pharmaceutical composition. Suitable sweetening agents include aspartame, glucose, glycerin, mannitol, sodium saccharin, sorbitol and sucrose.

  The term “colorant” generally refers to an excipient used to color a pharmaceutical composition. Suitable colorants include FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 2, D & C Green No. 5, D & C Orange No. 5, D & C Red No. 8, etc. FD & C. Pigments, caramels, red iron oxides, and natural colorants such as grape skin extract, beet red powder, beta-carotene, anato, carmine, turmeric, or paprika. The amount of colorant used can be varied as desired.

  The term “flavoring agent” generally refers to an excipient used to impart a favorable flavor (and often also an odor) to a pharmaceutical composition. Suitable flavoring agents generally include extracts from synthetic aromatic oils, flavoring aromatics, natural oils, whole plants or parts thereof (eg leaves, flowers, fruits, or combinations thereof). Is mentioned. Examples include cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, nutmeg oil, sage oil, tonsil oil, and cassia oil. Is mentioned. Other useful flavoring agents include vanilla, citrus fruit oil (eg lemon, orange, grape, lime or grapefruit oil), and fruit essence (eg apple, pear, peach, strawberry, raspberry, cherry, Plum, pineapple or apricot essence). Flavorings that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring agent can depend on many factors, including the desired sensory effect, and can be adapted as needed by one skilled in the art. Particularly preferred flavors are grape and cherry flavors, and citrus fruit flavors (eg orange flavors).

  Plasticizers can also be included in the pharmaceutical composition to modify the properties and characteristics of the polymer used in the coating layer or core of the composition. The term “plasticizer” generally refers to a compound used to plasticize or soften a component (eg, a polymer or binder) of a pharmaceutical composition. Suitable plasticizers are generally low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester plasticizers, glycol ethers, polypropylene glycols. , Multi-block polymers, single-block polymers, low molecular weight polyethylene glycols, citrate plasticizers, triacetin, propylene glycol and glycerin. Further, as such a plasticizer, preferably, ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other polyethylene glycol compounds, monopropylene Glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl butyrate, butyl butyrate, ethyl glycolate, acetyltributylcitrate, most preferably triethyl citrate Mention may also be made of dibutyl sebacate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are generally commercially available. It is also contemplated that combinations of plasticizers can be used in the formulations of the present invention. PEG-based plasticizers are either commercially available or described in various ways (eg, “Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications” (JM Harris, Ed .; Plenum Press, NY)). Method).

  The compositions of the present invention include oils such as fixed oils (eg, peanut oil, sesame oil, cottonseed oil, corn oil, most preferably olive oil), fatty acids (eg, oleic acid, stearic acid and isostearic acid), fatty acid esters ( For example, ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides) may also be included. Optional additional ingredients include alcohols (eg, ethanol, isopropanol, hexadecanol, glycerol and propylene glycol), glycerol ketals with or without the addition of pharmaceutically suitable surfactants, suspending agents or emulsifiers (Eg 2,2-dimethyl-1,3-dioxolane-4-methanol), ethers (eg poly (ethylene glycol) 450), petroleum hydrocarbons (eg mineral oil and petroleum jelly), water or mixtures thereof Can be mentioned.

  Soaps and synthetic detergents can be used as surfactants and as vehicles for detergent compositions. Suitable soaps include fatty acid alkali salts, ammonium salts, and triethanolamine salts. Suitable detergents include cationic detergents (eg, dimethyldialkylammonium halides, alkylpyridium halides and alkylamine acetates), anionic detergents (eg, alkyl, aryl and olefin sulfonates, alkyls, olefins, ethers and Monoglyceride sulfate, as well as sulfosuccinate). Preferred detergents include amphoteric detergents (eg alkyl-β-aminopropionate and 2-alkylimidazoline quaternary ammonium salts and mixtures thereof), most preferably nonionic detergents (eg fatty amines). ) Oxides, fatty acid alkanolamides and poly (oxyethylene) -block-poly (oxypropylene) copolymers.

  Various other ingredients can be added to the composition to optimize the release characteristics of the active drug of interest, including glyceryl monostearate, nylon, cellulose acetate butyrate, d, l -Poly (lactic acid), 1,6-hexanediamine, diethylenetriamine, starch, derivatized starch, acetylated monoglyceride, gelatin coacervate, poly (styrene-co-maleic acid), glycowax, castor wax , Stearyl alcohol, glycerol palmitostearate, polyethylene, polyvinyl acetate, polyvinyl chloride, 1,3-butylene-glycol dimethacrylate, ethylene glycol dimethacrylate and methacrylate hydrogels.

  It should be understood that compounds used in the field of pharmaceutical formulations can serve a variety of functions or purposes. Thus, whether a compound designated herein is mentioned only once or used to define more than one term, its purpose or function is merely the purpose of its designation. Or should not be construed as limited to function.

  The pharmaceutical composition of the present invention can assume any shape or form known in the pharmaceutical field. In particular, it can be a rod, plate, rotating paraboloid, spheroid etc. Preferably, the composition is a capsule (eg, hard or soft gelatin or vegetable capsule), tablet, rectangular tablet, caplet, pill, sphere, powder, or liquid suspension (eg, , Olive oil, glycerin, polyethylene glycol or other suitable nonionic vehicle in the form of an unhydrous suspension). Most preferably, the composition is in the form of a capsule. The final form of the composition may also include surface markings, cuttings, grooves, letters and / or numbers for decorative purposes, identification purposes and / or other purposes. The dosage form may include a finish to provide the desired gloss, color, taste or other aesthetic characteristics. Substances suitable for the preparation of finishes are generally known in the art.

Further preferred embodiments of the composition according to the invention are:
1) 4: 1 weight ratio of levodopa / carbidopa, especially levodopa 50 mg / carbidopa 12.5 mg (where carbidopa is an immediate release form of native powder and levodopa is bioadhesive (In the form of ion exchange resin / drug particles coated with an enteric coating layer)
2) 4: 1 weight ratio of levodopa / carbidopa, especially levodopa 100 mg / carbidopa 25 mg (where carbidopa is an immediate release form of unmodified powder, levodopa is a bioadhesive enteric coating layer) (This is in the form of a mixture of ion exchange resin / drug particles coated with and ion exchange resin / drug particles coated with an enteric coating layer with controlled release and bioadhesiveness)
3) 4: 1 weight ratio of levodopa / carbidopa, especially levodopa 200 mg / carbidopa 50 mg (where carbidopa is an immediate release form of unmodified powder, levodopa is a bioadhesive enteric coating layer) (This is in the form of a mixture of ion exchange resin / drug particles coated with and ion exchange resin / drug particles coated with an enteric coating layer that is controlled and bioadhesive)
4) 5-25: 20: 1-5 levodopa / entacapone / carbidopa, especially levodopa 50-250 mg, entacapone 200 mg, carbidopa 10-50 mg (where levodopa is a bioadhesive enteric In the form of a mixture of an ion exchange resin / drug particles coated with a coating layer and an ion exchange resin / drug particles coated with a controlled release bioadhesive enteric coating layer, Entacapone and carbidopa (In the form of ion exchange resin / drug particles coated with an adhesive enteric coating layer or in an unmodified powder form)
Represented by oral preparations, especially hard vegetable capsules.

  Alternatively, carbidopa can be replaced with benserazide in the above embodiment.

The oral pharmaceutical composition of the present invention can be produced by methods generally known in the art. A typical method for making the composition includes the following steps:
(i) contacting an ion exchange resin with an active drug to obtain an active drug / ion exchange resin complex;
(ii) optionally, coating the composite of step (i) with a coating layer containing a release modifying substance;
(iii) coating the composite of step (i) or the coated composite of step (ii) with a coating layer containing a bioadhesive material; and
(iv) optionally, coating the coated complex of step (iii) with a coating layer containing an enteric coating substance.

  In step (i), the active drug is preferably mixed with an aqueous suspension of the resin, and the resulting complex is washed and dried. The adsorption of the active drug to the resin can be detected by measuring the change in the pH of the reaction medium or by measuring the change in the concentration of counterion and / or active drug. Typically, the complex is washed with alcohol (eg, ethanol and / or water) to ensure removal of any unbound active drug. The composite is typically air dried at room temperature or elevated temperature in a tray. The binding can be performed, for example, according to batch or column methods known in the art.

In general, the binding of the active drug to the resin can follow one of four general reaction types. When linking the basic active drug to the cation exchange resin, these are: (a) resin (salt form, eg Na ⁺ -form) + active drug (salt form), (b) resin (salt form, eg Na ⁺ -Form) + active drug (free base), (c) resin (H ⁺ -form) + active drug (salt form), and (d) resin (H ⁺ -form) + active drug (free base). When coupling the acid of the active drug to an anion exchange resin, which are: (a) resin (salt form, for example, Cl ^- - Embodiment) + active drug (salt form), (b) resin (salt form, for example, Cl ^- - (Form) + active drug (free acid), (c) resin (OH ⁻ − form) + active drug (salt form); and (d) resin (OH ⁻ − form) + active drug (free acid). With the exception of (d), all of these reactions are by-products formed by competing the counter ion with the active drug for the binding site on the resin, thereby reducing the amount of active drug bound in equilibrium. Accompanied by. Thus, for both acidic and basic active drugs, true stoichiometric binding of the active drug to the resin is achieved only by reaction (d).

  In steps (ii)-(iv), the particles can be coated using conventional coating solvents and coating methods (eg, fluidized bed coating or spray coating). Fluid bed coating techniques are taught, for example, in US 3,089,824, US 3,117,027 and US 3,253,944. The coating is typically applied to the active drug and ion exchange resin complex, but can alternatively be applied to the resin prior to complexing with the active drug. The coating mixture is typically applied as a solution, dispersion or emulsion in a coating solvent. Examples of suitable coating solvents include methanol, ethanol, isopropanol, isobutanol, n-butyl acetate, ethyl acetate, acetone, methyl ethyl ketone, hexane, methyl isobutyl ketone, carbon tetrachloride, methylene chloride, ethylene chloride, trichloroethylene, tetrahydrofuran, 2-nitropropane, toluene, xylene, and mixtures thereof (for example, a mixture of methylene chloride and acetone). Methanol, ethanol, isopropanol, isobutanol, n-butyl acetate and ethyl acetate are preferred.

  The invention is further illustrated by the methods of the following examples.

  Levodopa release was measured spectrophotometrically at 280 nm.

Example 1
A) Preparation of Levodopa Drug Resin Complex (LDRC) 1200 ml of deionized water with polystyrene polystyrene sulfonate cation exchange resin (400 g) (125-400 mesh) cross-linked with divinylbenzene with gentle stirring for 1 hour Mixed with water. The resin was precipitated and water was decanted. Dilute HCl was prepared by adding 300 ml concentrated HCl to 1200 ml deionized water and mixing. The resin was mixed with 250 ml of dilute HCl for 30 minutes, then allowed to settle, the supernatant was decanted and this process was repeated until all the dilute HCl was used up. The resin was washed by mixing the resin with 500 ml deionized water for 10 minutes, allowing the resin to settle and decanting the supernatant eight times or until the supernatant was neutral with litmus paper.

  A mixture of 300 ml ethanol and 300 ml deionized water was added to the resin, 250 g levodopa was added and treated with the resin for 4 hours with mixing for 1 minute every 30 minutes. After allowing the resin to settle overnight, the supernatant was decanted. The resin is mixed with 300 ml of a water / ethanol (3: 2) mixture, the resin is precipitated, the supernatant is decanted, and the supernatant is evaporated until no levodopa crystals are seen under the microscope. Washing was performed by repeating the process. The resulting levodopa drug resin complex was dried in an oven at 60 ° C. Moisture content (LOD [loss on drying]): 5 ± 0.5 wt%, levodopa content (HPLC): 40 ± 1 wt%. The resulting complex is stable to exposure to air for at least 6 months at room temperature It turns out that.

  The levodopa ionic binding in the composite was tested by adding increasing amounts of electrolyte (NaCl) to a slurry of LDRC in deionized water. The release of levodopa is shown in FIG.

レボドパ薬物樹脂複合体(LDRC)を流動体化し、Mini-Glattコーティング装置を用いてコーティング分散液をスプレーし、そのままで45〜50℃まで乾燥させた。該生成物を、40メッシュのステンレススチールスクリーンによって篩い分けした。顕微鏡検査によって、中程度の凝集を有する均一に被覆された粒子が示された。実施例1B-2〜1B-4で得られた被覆された生成物を、60℃で2時間、さらに保存処理（cured）した。
実施例1B-1および1B-3で得られた被覆LDRCの、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 50 rpm, 37℃, pH 5.5, イオン強度 0.075)を図2および3に示す。実施例1B-2〜1B-4で得られた被覆LDRCの、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 50 rpm, 37℃, pH 6.0, イオン強度 0.075)を図4に示す。 B) Coating with a modified release coating layer

Levodopa drug resin complex (LDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus and allowed to dry as it was to 45-50 ° C. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination showed uniformly coated particles with moderate agglomeration. The coated product obtained in Examples 1B-2 to 1B-4 was further cured at 60 ° C. for 2 hours.
Figure 2 shows the dissolution profile (USP method # 2, paddle rotation speed 50 rpm, 37 ° C, pH 5.5, ionic strength 0.075) of the coated LDRC obtained in Examples 1B-1 and 1B-3 in phosphate buffer. Shown in 3. Figure 4 shows the dissolution profile (USP method # 2, paddle rotation speed 50 rpm, 37 ° C, pH 6.0, ionic strength 0.075) of the coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer. Show.

*アリルエーテルおよびペンタエリスリトールで架橋されたアクリル酸の高分子量ポリマー
レボドパ薬物樹脂複合体(LDRC)を、流動体化し、Mini-Glattコーティング装置を用いてコーティング分散液をスプレーし、そのままで50℃まで乾燥させた。該生成物を、40メッシュのステンレススチールスクリーンによって篩い分けした。顕微鏡検査によって、中程度の凝集を有する均一な被覆粒子が示された。
実施例1C-3および1C-5で得られた被覆LDRCの、リン酸バッファー中の溶解プロファイル(USP メソッド #2, パドル回転速度 50 rpm, 37℃, pH 6.0, イオン強度 0.075)を図5および6に示す。 C) Coating with bioadhesive coating layer

* High molecular weight polymer of acrylic acid cross-linked with allyl ether and pentaerythritol Levodopa Drug Resin Complex (LDRC) is fluidized and sprayed with a coating dispersion using a Mini-Glatt coating device, up to 50 ° C Dried. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination showed uniform coated particles with moderate agglomeration.
The dissolution profile (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., pH 6.0, ionic strength 0.075) of the coated LDRC obtained in Examples 1C-3 and 1C-5 in phosphate buffer is shown in FIG. 5 and Shown in 6.

*市販のメタクリル酸コポリマーおよび水中での分散を容易にするために作製された分散剤
レボドパ薬物樹脂複合体(LDRC)を流動体化し、Mini-Glattコーティング装置を用いてコーティング分散液をスプレーし、そのままで55℃まで乾燥させた。該生成物を、40メッシュのステンレススチールスクリーンによって篩い分けした。顕微鏡検査によって、中程度の凝集を有する均一な被覆粒子が示された。
実施例1D-2〜1D-4で得られた被覆LDRCの、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 50 rpm, 37℃, 溶解媒質 0〜1時間: 0.1 N HCl, 1〜12時間: リン酸バッファー pH 6.25, イオン強度 0.075)を図7に示す。実施例1D-1および1D-4で得られた被覆LDRCの、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 50 rpm, 37℃, 溶解媒質 0〜1時間: 0.1 N HCl, 1〜12時間: リン酸バッファー pH 6.25, イオン強度 0.075)を図8に示す。 D) Coating with enteric coating layer

* Commercially available methacrylic acid copolymer and dispersant made to facilitate dispersion in water.Levodopa drug resin complex (LDRC) is fluidized and sprayed with a coating dispersion using a Mini-Glatt coating device, It was dried as it was to 55 ° C. The product was sieved through a 40 mesh stainless steel screen. Microscopic examination showed uniform coated particles with moderate agglomeration.
Dissolution profile of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., dissolution medium 0 to 1 hour: 0.1 N HCl, 1-12 hours: Phosphate buffer pH 6.25, ionic strength 0.075) is shown in FIG. Dissolution profile of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method # 2, paddle rotation speed 50 rpm, 37 ° C., dissolution medium 0-1 hour: 0.1 N HCl, 1-12 hours: Phosphate buffer pH 6.25, ionic strength 0.075) is shown in FIG.

1つ以上のレボドパ薬物樹脂複合体を、記載の通り、カルビドパおよびステアリン酸マグネシウムもしくはタルカムと乾燥混合させた。得られた混合物を硬ゼラチンカプセルに充填した。 E) Hard gelatin capsules containing levodopa and carbidopa

One or more levodopa drug resin complexes were dry mixed with carbidopa and magnesium stearate or talcum as described. The resulting mixture was filled into hard gelatin capsules.

レボドパ薬物樹脂複合体を、記載の通り、カルビドパおよび賦形剤と乾燥混合させた。得られた混合物を錠剤へと圧縮した。 F) Tablets containing levodopa and carbidopa

The levodopa drug resin complex was dry mixed with carbidopa and excipients as described. The resulting mixture was compressed into tablets.

Examples 2-5
A) Manufacture of drug resin complex (DRC)
2A) Production of Ropinirole Drug Resin Complex (RoDRC) Sodium polystyrenesulfonate cation exchange resin (100 g) (125-400 mesh) cross-linked with divinylbenzene is added to 500 ml deionized degassed water, occasionally under argon And mixed for 1 hour. The resulting slurry was transferred to a 250 ml glass column and washed with 200 ml deionized degassed water. 40 g ropinirole hydrochloride was dissolved in 300 ml deionized degassed water and passed through the column at a rate of 10 ml / min. The column was washed with 1000 ml deionized degassed water. The resulting drug resin complex was removed from the column and first dried with filter paper and then with silica under reduced pressure to a moisture content of 5% by weight.
Dissolution profile of the resulting uncoated ropinirole drug resin complex (RoDRC; USP method # 2, paddle rotation speed 75 rpm, 37 ° C, dissolution medium 0 to 1 hour: 0.1 N HCl, 1 to 10 hours: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075) is shown in FIG.

3A) Production of alendronate drug resin complex (AlDRC)
50 g cholestyramine anion exchange resin (Cl ⁻ -form, 99% <100 μ, 56% <50 μ) was washed with 5 × 200 ml degassed water. After 5 hours, the last water portion was decanted. 300 ml of degassed water and 16.25 g of alendronate sodium were added to the resin. The resulting slurry was mixed for 60 minutes at room temperature, centrifuged and the solvent decanted. This was repeated three more times until a total of 65 g of alendronate sodium was used. The resulting drug resin complex was washed with 3 l of water, dried first with filter paper and then with silica under reduced pressure to a moisture content of 5% by weight.

4A) Preparation of Risperidone Drug Resin Complex (RiDRC) Polystyrene sulfonate cation exchange resin (H ⁺ -form) (100 g) cross-linked with divinylbenzene was washed with 500 ml of deionized degassed water for 30 minutes. The water was decanted and the resin was washed with 300 ml of 96% ethanol. 100 g risperidone was added to 300 ml 96% ethanol. The slurry was heated to 60 ° C., added to the resin and mixed for 12 hours under argon. The solvent was decanted and the resin was washed with 5 x 250 ml 96% ethanol. The last ethanol portion was left overnight under argon. The ethanol was decanted and the resulting drug resin complex was dried to a water content of 5% by weight, first with filter paper and then with silica under reduced pressure.

5A) Preparation of Olanzapine Drug Resin Complex (OzDRC) Polystyrene sulfonate cation exchange resin (H ⁺ -form) (100 g) cross-linked with divinylbenzene was washed with 500 ml of degassed 96% ethanol. The ethanol was decanted. 80 g of olanzapine was dispersed in 500 ml of degassed 96% ethanol at 40 ° C. and added to the resin. The resulting slurry was mixed at 40 ° C. under argon for 5 hours and then left at room temperature overnight. The solvent was decanted and the resulting olanzapine drug resin complex was washed with 10 × 500 ml of degassed 96% ethanol. The resulting drug resin complex was first dried with filter paper and then with silica under reduced pressure to a moisture content of 5% by weight.

実施例1Bと同様に、ロピニロール薬物樹脂複合体(RoDRC)を流動体化し、Mini-Glattコーティング装置を用いてコーティング分散液をスプレーした。 B) Coating with a modified release coating layer
2B) RoDRC coating with modified release coating layer

As in Example 1B, ropinirole drug resin complex (RoDRC) was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus.

3B) AlDRC coating with modified release coating layer
25 g ethylcellulose was mixed thoroughly with 30 ml 99% ethanol and 0.5 g glycerin (used as plasticizer). The resulting mixture was added to 40 g of the alendronate drug resin complex produced in Example 3A and mixed until the mixture was homogeneous. The wet mass was pushed through a 425 μ sieve and dried at 60 ° C. for 2 hours. The resulting granules were sieved with a 425 μ sieve.

*アリルエーテルおよびペンタエリスリトールと架橋したアクリル酸の高分子量ポリマー

実施例1Cと同様に、薬物樹脂複合体を流動体化し、Mini-Glattコーティング装置を用いて、コーティング分散液をスプレーした。 C) Coating with bioadhesive coating layer

* High molecular weight polymer of acrylic acid cross-linked with allyl ether and pentaerythritol

As in Example 1C, the drug resin complex was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus.

*市販のメタクリル酸コポリマーおよび水中での分散を容易にするために作製された分散剤

実施例1Dと同様に、薬物樹脂複合体を流動体化し、Mini-Glattコーティング装置を用いて、コーティング分散液をスプレーした。
篩い分けの前および後の実施例2Dで得られた被覆ロピニロール薬物樹脂複合体の、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 75 rpm, 37℃, 溶解媒質 0〜1時間: 500 ml 0.1 N HCl, 1〜10時間: バッファー混合物 [500 ml 0.1 N HCl + 500 ml リン酸バッファー], pH 5.6, イオン強度 0.075)を図9に示す。
実施例3D、4Dおよび5Dで得られた被覆薬物樹脂複合体の溶解プロファイルを、図10〜12に示す。 D) Coating with enteric coating layer

* Commercial methacrylic acid copolymers and dispersants made to facilitate dispersion in water

As in Example 1D, the drug resin complex was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus.
Dissolution profile of coated ropinirole drug resin complex obtained in Example 2D before and after sieving in phosphate buffer (USP method # 2, paddle rotation speed 75 rpm, 37 ° C, dissolution medium 0 to 1 hour : 500 ml 0.1 N HCl, 1-10 hours: FIG. 9 shows the buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075).
The dissolution profiles of the coated drug resin complexes obtained in Examples 3D, 4D and 5D are shown in FIGS.

*市販のメタクリル酸コポリマーおよび水中での分散を容易にするために作製された分散剤

実施例1Dと同様に、薬物樹脂複合体を流動体化し、Mini-Glattコーティング装置を用いて、コーティング分散液をスプレーした。
篩い分けの前および後の実施例2Dで得られた被覆ロピニロール薬物樹脂複合体の、リン酸バッファー中における溶解プロファイル(USP メソッド #2, パドル回転速度 75 rpm, 37℃, 溶解媒質 0〜1時間: 500 ml 0.1 N HCl, 1〜10時間: バッファー混合物 [500 ml 0.1 N HCl + 500 ml リン酸バッファー], pH 5.6, イオン強度 0.075)を図9に示す。
実施例3D、4Dおよび5Dで得られた被覆薬物樹脂複合体の溶解プロファイルを、図10〜12に示す。

本発明は以下の態様を含む：
項１．少なくとも1つの活性薬物とイオン交換樹脂との複合体の被覆粒子を含有する経口医薬組成物であって、該粒子は少なくとも1つの生体接着性物質を含有する生体接着性コーティング層で被覆されている、該経口医薬組成物。
項２．該被覆粒子がさらに、生体接着性層を覆うように位置していて少なくとも1つの腸溶コーティング物質を含有する腸溶コーティング層を含む、項１に記載の組成物。
項３．該被覆粒子の少なくとも一部がさらに、該複合体と該生体接着性層の間に位置していて少なくとも1つの放出改変物質を含有する放出改変コーティング層を含む、項２に記載の組成物。
項４．該生体接着性物質が、平均分子量で少なくとも約10,000ダルトン、好ましくは少なくとも約50,000ダルトン、より好ましくは少なくとも約100,000ダルトン、さらにより好ましくは少なくとも約1,000,000ダルトン、そして最も好ましくは約1,000,000〜約10,000,000ダルトンの重量である、修飾および非修飾の合成ポリカルボキシレートポリマーからなる群から選択される、項３に記載の組成物。
項５．該生体接着性物質が、アクリル酸またはアルキルアクリル酸の適宜架橋したホモポリマー、ならびにアクリル酸またはメタクリル酸とアクリル酸(C₁₀-C₃₀)アルキルとの適宜架橋したコポリマーからなる群から選択される、請求項3または4に記載の組成物。
項６．該腸溶コーティング物質が、アニオン性セルロース誘導体、アニオン性ビニル樹脂およびアニオン性アクリル樹脂からなる群から選択される、項２〜５のいずれか一項に記載の組成物。
項７．該腸溶コーティング物質が、酢酸フタル酸セルロース、二酢酸フタル酸セルロース、三酢酸フタル酸セルロース、フタル酸メチルセルロース、フタル酸ヒドロキシプロピルセルロース、フタル酸ヒドロキシプロピルメチルセルロース、酢酸ヘキサヒドロフタル酸セルロース、ヘキサヒドロフタル酸ヒドロキシプロピルメチルセルロース、およびそれらの医薬的に許容される塩、酢酸フタル酸ポリビニル、ポリ(メタクリル酸-共-アクリル酸エチル)、ならびにポリ(メタクリル酸-共-メタクリル酸メチル)からなる群から選択される、項６に記載の組成物。
項８．該腸溶コーティング層が該生体接着性層を直接覆うように位置している、項２に記載の組成物。
項９．該生体接着性物質が、平均分子量で少なくとも約10,000ダルトン、好ましくは少なくとも約50,000ダルトン、より好ましくは少なくとも約100,000ダルトン、さらにより好ましくは少なくとも約1,000,000ダルトン、そして最も好ましくは約1,000,000〜約10,000,000ダルトンの重量である、修飾および非修飾の合成ポリカルボキシレートポリマーからなる群から選択される、項８に記載の組成物。
項１０．該生体接着性物質が、アクリル酸またはアルキルアクリル酸の適宜架橋したホモポリマー、ならびにアクリル酸またはメタクリル酸とアクリル酸(C₁₀-C₃₀)アルキルとの適宜架橋したコポリマーからなる群から選択される、項８または９に記載の組成物。
項１１．該腸溶コーティング物質が、アニオン性セルロース誘導体、アニオン性ビニル樹脂およびアニオン性アクリル樹脂からなる群から選択される、項８〜１０のいずれか一項に記載の組成物。
項１２．該腸溶コーティング物質が、酢酸フタル酸セルロース、二酢酸フタル酸セルロース、三酢酸フタル酸セルロース、フタル酸メチルセルロース、フタル酸ヒドロキシプロピルセルロース、フタル酸ヒドロキシプロピルメチルセルロース、酢酸ヘキサヒドロフタル酸セルロース、ヘキサヒドロフタル酸ヒドロキシプロピルメチルセルロース、およびそれらの医薬的に許容される塩、酢酸フタル酸ポリビニル、ポリ(メタクリル酸-共-アクリル酸エチル)、ならびにポリ(メタクリル酸-共-メタクリル酸メチル)からなる群から選択される、項１１に記載の組成物。
項１３．該被覆粒子の少なくとも一部がさらに、該複合体と該生体接着性層の間に位置していて少なくとも1つの放出改変物質を含有する放出改変コーティング層を含む、項１に記載の組成物。
項１４．該生体接着性物質が、平均分子量で少なくとも約10,000ダルトン、好ましくは少なくとも約50,000ダルトン、より好ましくは少なくとも約100,000ダルトン、さらにより好ましくは少なくとも約1,000,000ダルトン、そして最も好ましくは約1,000,000〜約10,000,000ダルトンの重量である、修飾および非修飾の合成ポリカルボキシレートポリマーからなる群から選択される、項１３に記載の組成物。
項１５．該生体接着性物質が、アクリル酸またはアルキルアクリル酸の適宜架橋したホモポリマー、ならびにアクリル酸またはメタクリル酸とアクリル酸(C₁₀-C₃₀)アルキルとの適宜架橋したコポリマーからなる群から選択される、項１３または１４に記載の組成物。
項１６．該放出改変物質が遅延放出物質または徐放性物質から選択される、項３〜７および１３〜１５のいずれか一項に記載の組成物。
項１７．該放出改変物質が、エチルセルロース、メチルセルロース、ヒドロキシプロピルメチルセルロース、酢酸セルロース、酢酸フタル酸セルロース、酢酸トリメリット酸セルロース、フタル酸ヒドロキシプロピルメチルセルロース、酢酸コハク酸ヒドロキシプロピルメチルセルロース、ポリ(メタクリル酸-共-アクリル酸エチル)、ポリ(メタクリル酸-共-メタクリル酸メチル)、ポリ塩化ビニル、酢酸フタル酸ポリビニル、ポリ(ビニルピロリドン-共-ビニルアセテート)、シリコンエラストマー、シェラック、ゼイン、ロジンエステル、およびそれらの混合物からなる群から選択される、項１６に記載の組成物。
項１８．該放出改変物質が、メチルセルロース、エチルセルロース、およびそれらの混合物からなる群から選択される、項１７に記載の組成物。
項１９．放出改変物質の量および/または組成が異なる少なくとも2つのグループの被覆粒子を含有する、項１〜１８のいずれか一項に記載の組成物。
項２０．該イオン交換樹脂が、イオン基で修飾されたアクリル酸、メタクリル酸およびスチレンのポリマーおよびコポリマー、イオン基で修飾されたセルロース、イオン基で修飾されたデキストラン、ならびにイオン基で修飾されたシリカゲルからなる群から選択され、ここで、該イオン基はスルホン酸基、第三級アミン基または第四級アンモニウム基から選択される、項１〜１９のいずれか一項に記載の組成物。
項２１．該イオン交換樹脂がスチレンおよびジビニルベンゼンの架橋したスルホン化コポリマーである、項２０に記載の組成物。
項２２．該活性薬物とイオン交換樹脂との複合体の粒子の平均粒子サイズが、好ましくは、約10〜約3000 μm、とりわけ約30〜約2000 μm、そして最も好ましくは約50〜約1000 μmである、項１〜２１のいずれか一項に記載の組成物。
項２３．該被覆粒子の平均粒子サイズが、好ましくは、約20〜約5000 μm、とりわけ約50〜約4000 μm、そして最も好ましくは約70〜約3000 μmである、項１〜２２のいずれか一項に記載の組成物。
項２４．該被覆粒子が、1.1〜2.0、好ましくは1.2〜1.8の範囲の比重を有する、項１〜２３のいずれか一項に記載の組成物。
項２５．該被覆粒子が、約1〜200 m²/gの範囲の比表面積を示す、項１〜２４のいずれか一項に記載の組成物。
項２６．該活性薬物が、オンダンセトロン、グラニセトロン、トロピセトロン、ドラセトロン、パロノセトロン、アプレピタント、スルファサラジン、ドキサゾシン、アテノロール、ビソプロロール、ヒドロクロロチアジド、カルベジロール、アムロジピン、フェロジピン、ニフェジピン、ベラパミル、ジルチアゼム、エナラプリル、リシノプリル、ラミプリル、キナプリル、シラザプリル、フォシノプリル、トランドラプリル、ロサルタン、バルサルタン、シンバスタチン、ロバスタチン、フルバスタチン、アトルバスタチン、ロスバスタチン、ゲムフィブロジル、フェノフィブラート、コレスチラミン、オキシブチニン、プロピベリン、ソリフェナシン、トロスピウム、ダリフェナシン、シルデナフィル、フェントラミン、タムスロシン、フィナステリド、シクロホスファミド、クロラムブシル、メルファラン、ブスルファン、ロムスチン、テモゾロミド、メトトレキサート、メルカプトプリン、チオグアニン、クラドリビン、フルダラビン、シタラビン、5-フルオロウラシル、ゲムシタビン、カペシタビン、ビンブラスチン、ビンクリスチン、ビンデシン、エトポシド、パクリタキセル、ドセタキセル、アクチノマイシンD、ドキソルビシン、ダウノルビシン、エピルビシン、イダルビシン、ミトキサントロン、ブレオマイシン、マイトマイシン、シスプラチン、カルボプラチン、オキサリプラチン、プロカルバジン、リツキシマブ、トラスツズマブ、セツキシマブ、ベバシズマブ、スニチニブ、ソラフェニブ、ダサチニブ、ラパチニブ、ニロチニブ、テムシロリムス、アムサクリン、アスパラギナーゼ、ヒドロキシウレア、エストラムスチン、トポテカン、イリノテカン、イマチニブ、ボルテゾミブ、エルロチニブ、アナグレリド、メゲストロール、タモキシフェン、フルタミド、ニルタミド、ビカルタミド、アナストロゾール、レトロゾール、エキセメスタン、ミコフェノール酸モフェチル、シロリムス、エベロリムス、シクロスポリン、タクロリムス、アザチオプリン、エチドロン酸、クロドロン酸、パミドロン酸、アレンドロン酸、チルドロン酸、イバンドロン酸、リセドロン酸、ゾレドロン酸、モルヒネ、ヒドロモルホン、オキシコドン、ペチジン、フェンタニル、ペンタゾシン、ブプレノルフィン、トラマドール、アセチルサリチル酸、メタミゾール、パラセタモール、スマトリプタン、メチルフェノバルビタール、フェノバルビタール、プリミドン、フェニトイン、エトスクシミド、クロナゼパム、カルバマゼピン、オクスカルバゼピン、バルプロ酸、ビガバトリン、プロガビド、チアガビン、スルチアム、フェナセミド、ラモトリギン、フェルバメート、トピラマート、ガバペンチン、フェネトライド、レベチラセタム、ゾニサミド、プレガバリン、スチリペントール、ラコサミド、ベクラミド、トリヘキシフェニジル、ビペリデン、レボドパ、カルビドパ、ベンセラジド、エンタカポン、アマンタジン、ブロモクリプチン、ペルゴリド、ジヒドロエルゴクリプチン、ロピニロール、プラミペキソール、カベルゴリン、アポモルヒネ、ピリベジル、ロチゴチン、セレギリン、ラサギリン、トルカポン、エンタカポン、ブジピン、レボメプロマジン、クロルプロマジン、プロマジン、フルフェナジン、ペラジン、ハロペリドール、セルチンドール、ジプラシドン、ズクロペンチキソール、クロザピン、オランザピン、クエチアピン、ロキサピン、スルピリド、アミスルプリド、リチウム、プロチペンジル、リスペリドン、クロチアピン、モサプラミン、ゾテピン、アリピプラゾール、パリペリドン、ジアゼパム、アルプラゾラム、メプロバメート、フルラゼパム、ニトラゼパム、ミダゾラム、ゾルピデム、クロミプラミン、アミトリプチリン、マプロチリン、フルオキセチン、シタロプラム、パロキセチン、セルトラリン、アラプロクラート、フルボキサミン、エトペリドン、エスシタロプラム、ミルタザピン、ベンラファキシン、メチルフェニデート、モダフィニル、ネオスチグミン、ピリドスチグミン、ジスルフィラム、ナロキソン、メサドン、リルゾール、アバカビル、アシクロビル、アトロピン、ブスピロン、カフェイン、カプトプリル、クロロキン、クロルフェナミン、デシプラミン、ジフェンヒドラミン、ジソピラミド、ドキセピン、ドキシサイクリン、エフェドリン、エルゴノビン、エタンブトール、グルコース、イミプラミン、ケトロラク、ケトプロフェン、ラベタロール、レボフロキサシン、メトプロロール、メトロニダゾール、ミノサイクリン、ミソプロストール、フェナゾン、フェニルアラニン、プレドニゾロン、プリマキン、プロプラノロール、キニジン、ロシグリタゾン、サリチル酸、テオフィリン、ジドブジン、コデイン、デキストロメトルファン、ヒドロコドン、ヒドララジン、メタプロテレノール、フェニルプロパノールアミン、プソイドエフェドリン、およびそれらの混合物からなる群から選択される、項１〜２５のいずれか一項に記載の組成物。
項２７．該活性薬物が、レボドパ、カルビドパ、ベンセラジド、エンタカポン、およびそれらの混合物からなる群から選択される、項２６に記載の組成物。
項２８．該活性薬物が、アレンドロネート、オランザピン、リスペリドンおよびロピニロールからなる群から選択される、項２６に記載の組成物。
項２９．異なる活性薬物を含む少なくとも2つのグループの被覆粒子を含有する、項１〜２８のいずれか一項に記載の組成物。
項３０．さらに、活性薬物またはその医薬的に許容される塩もしくは溶媒和物を被覆粒子の外側に含有する、項１〜２９のいずれか一項に記載の組成物。
項３１．レボドパおよびカルビドパもしくはベンセラジドを、20:1〜1:1、好ましくは15:1〜2:1、そして最も好ましくは10:1〜4:1の比で含有する、項１〜３０のいずれか一項に記載の組成物。
項３２．該被覆粒子が、被覆粒子の総重量に基づいて、
(a)1〜50重量％、とりわけ5〜40重量％、好ましくは10〜20重量％の該少なくとも1つの活性薬物;
(b)1〜50重量％、とりわけ10〜35重量％、好ましくは15〜25重量％の該イオン交換樹脂;
(c)0〜50重量％、とりわけ1〜50重量％、好ましくは10〜40重量％、より好ましくは15〜30重量％の該放出改変物質;
(d)0.5〜30重量％、とりわけ1〜10重量％、好ましくは2〜8重量％の該生体接着性物質;ならびに、
(e)0〜80重量％、とりわけ1〜80重量％、好ましくは10〜60重量％、より好ましくは30〜50重量％の該腸溶コーティング物質
を含有する、項１〜３１のいずれか一項に記載の組成物。
項３３．(i)活性薬物をイオン交換樹脂と接触させて活性薬物/イオン交換樹脂複合体を得る工程;
(ii)適宜、放出改変物質を含有するコーティング層で工程(i)の複合体をコーティングする工程;
(iii)生体接着性物質を含有するコーティング層で工程(i)の複合体または工程(ii)の被覆された複合体をコーティングする工程;ならびに、
(iv)適宜、腸溶コーティング物質を含有するコーティング層で工程(iii)の被覆された複合体をコーティングする工程
を含有する、項１〜３２のいずれか一項に記載の組成物の製造方法。 D) Coating with enteric coating layer

* Commercial methacrylic acid copolymers and dispersants made to facilitate dispersion in water

As in Example 1D, the drug resin complex was fluidized and sprayed with the coating dispersion using a Mini-Glatt coating apparatus.
Dissolution profile of coated ropinirole drug resin complex obtained in Example 2D before and after sieving in phosphate buffer (USP method # 2, paddle rotation speed 75 rpm, 37 ° C, dissolution medium 0 to 1 hour : 500 ml 0.1 N HCl, 1-10 hours: FIG. 9 shows the buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075).
The dissolution profiles of the coated drug resin complexes obtained in Examples 3D, 4D and 5D are shown in FIGS.

The present invention includes the following embodiments:
Item 1. An oral pharmaceutical composition comprising coated particles of a complex of at least one active drug and an ion exchange resin, wherein the particles are coated with a bioadhesive coating layer containing at least one bioadhesive substance The oral pharmaceutical composition.
Item 2. Item 2. The composition according to Item 1, wherein the coated particle further comprises an enteric coating layer positioned to cover the bioadhesive layer and containing at least one enteric coating substance.
Item 3. Item 3. The composition of Item 2, wherein at least a portion of the coated particles further comprises a release modifying coating layer located between the composite and the bioadhesive layer and containing at least one release modifying material.
Item 4. The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. Item 4. The composition according to Item 3, selected from the group consisting of synthetic and unmodified synthetic polycarboxylate polymers that are by weight.
Item 5. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. 5. A composition according to claim 3 or 4.
Item 6. Item 6. The composition according to any one of Items 2 to 5, wherein the enteric coating substance is selected from the group consisting of an anionic cellulose derivative, an anionic vinyl resin, and an anionic acrylic resin.
Item 7. The enteric coating substance is cellulose acetate phthalate, cellulose diacetate, cellulose triacetate, methyl phthalate, hydroxypropyl cellulose, hydroxypropyl methyl phthalate, cellulose hexahydrophthalate, hexahydrophthalate Hydroxypropylmethylcellulose acid and their pharmaceutically acceptable salts, selected from the group consisting of polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate), and poly (methacrylic acid-co-methyl methacrylate) Item 7. The composition according to Item 6.
Item 8. Item 3. The composition according to Item 2, wherein the enteric coating layer is positioned so as to directly cover the bioadhesive layer.
Item 9. The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. Item 9. The composition according to Item 8, wherein the composition is selected from the group consisting of modified and unmodified synthetic polycarboxylate polymers by weight.
Item 10. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. Item 10. The composition according to Item 8 or 9.
Item 11. Item 11. The composition according to any one of Items 8 to 10, wherein the enteric coating substance is selected from the group consisting of an anionic cellulose derivative, an anionic vinyl resin, and an anionic acrylic resin.
Item 12. The enteric coating substance is cellulose acetate phthalate, cellulose diacetate, cellulose triacetate, methyl phthalate, hydroxypropyl cellulose, hydroxypropyl methyl phthalate, cellulose hexahydrophthalate, hexahydrophthalate Hydroxypropylmethylcellulose acid and their pharmaceutically acceptable salts, selected from the group consisting of polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate), and poly (methacrylic acid-co-methyl methacrylate) Item 12. The composition according to Item 11, wherein
Item 13. Item 2. The composition of Item 1, wherein at least a portion of the coated particles further comprises a modified release coating layer located between the composite and the bioadhesive layer and containing at least one release modifying material.
Item 14. The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. Item 14. The composition according to Item 13, wherein the composition is selected from the group consisting of modified and unmodified synthetic polycarboxylate polymers by weight.
Item 15. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. Item 15. The composition according to Item 13 or 14.
Item 16. Item 16. The composition according to any one of Items 3 to 7 and 13 to 15, wherein the release-modifying material is selected from delayed-release materials or sustained-release materials.
Item 17. The release-modifying substance is ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, poly (methacrylic acid-co-acrylic acid) Ethyl), poly (methacrylic acid-co-methyl methacrylate), polyvinyl chloride, polyvinyl acetate phthalate, poly (vinyl pyrrolidone-co-vinyl acetate), silicone elastomer, shellac, zein, rosin ester, and mixtures thereof Item 17. The composition according to Item 16, selected from the group consisting of:
Item 18. Item 18. The composition according to Item 17, wherein the release-modifying substance is selected from the group consisting of methylcellulose, ethylcellulose, and mixtures thereof.
Item 19. Item 19. The composition according to any one of Items 1 to 18, comprising at least two groups of coated particles that differ in the amount and / or composition of the release modifying substance.
Item 20. The ion exchange resin comprises polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups, and silica gel modified with ionic groups Item 20. The composition according to any one of Items 1 to 19, wherein the composition is selected from the group, wherein the ionic group is selected from a sulfonic acid group, a tertiary amine group, or a quaternary ammonium group.
Item 21. Item 21. The composition according to Item 20, wherein the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinylbenzene.
Item 22. The average particle size of the particles of the active drug and ion exchange resin complex is preferably from about 10 to about 3000 μm, especially from about 30 to about 2000 μm, and most preferably from about 50 to about 1000 μm. Item 22. The composition according to any one of Items 1 to 21.
Item 23. Item 21. The average particle size of the coated particles is preferably about 20 to about 5000 μm, especially about 50 to about 4000 μm, and most preferably about 70 to about 3000 μm. The composition as described.
Item 24. Item 24. The composition according to any one of Items 1 to 23, wherein the coated particles have a specific gravity in the range of 1.1 to 2.0, preferably 1.2 to 1.8.
Item 25. Item 25. The composition of any one of Items 1 to 24, wherein the coated particles exhibit a specific surface area in the range of about 1 to 200 m ² / g.
Item 26. The active drug is ondansetron, granisetron, tropisetron, dolasetron, palonosetron, aprepitant, sulfasalazine, doxazosin, atenolol, bisoprolol, hydrochlorothiazide, carvedilol, amlodipine, felodipine, nifedipine, verapamil, diltiazem, enalapril, prilapril, prilapril, prilapril Cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, fenofibrate, cholestyramine, oxybutynin, propiverine, solifenacin, trospium, darifenacin, sildenatamlo Teride, cyclophosphamide, chlorambucil, melphalan, busulfan, lomustine, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, capecitabine, vinblastine, vincristine, vindecine, cidetaxel , Actinomycin D, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, cisplatin, carboplatin, oxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, soratibib Amsacrine, Sparaginase, hydroxyurea, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, megestrol, tamoxifen, flutamide, nilutamide, bicalutamide, anastrozole, letrozole, exemestane, mycophenolate mofetil, sirolimus , Cyclosporine, tacrolimus, azathioprine, etidronic acid, clodronic acid, pamidronic acid, alendronic acid, tiludronic acid, ibandronic acid, risedronic acid, zoledronic acid, morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprenorphine, tramadol, acetylsalicylic acid , Metamizole, paracetamol, sumatriptan, methylphenobarbital , Phenobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, tiagabine, sultiam, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, phenethride, penezatum , Lacosamide, bechramid, trihexyphenidyl, biperidene, levodopa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocryptin, ropinirole, pramipexole, cabergoline, apomorphine, piribezil, rotigolasine, rotigolasine, rotigothine , Bulgepine, levomepromazine, Lupromazine, promazine, fluphenazine, perazine, haloperidol, sertindol, ziprasidone, zuclopentixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium, protipendil, risperidone, clothiapine, mosapramine, zotepine, aripiprazole, paliperidone , Diazepam, alprazolam, meprobamate, flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaprocrate, fluvoxamine, etoperidone, escitalopramil, escitalopramil Neostigmine, pyri Stigmine, disulfiram, naloxone, methadone, riluzole, abacavir, acyclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, troimipritol, glucose Ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorhradiol, hydrocodone, hydrocodone , Item 26. The composition according to any one of Items 1 to 25, selected from the group consisting of phenylpropanolamine, pseudoephedrine, and mixtures thereof.
Item 27. Item 27. The composition according to Item 26, wherein the active drug is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone, and mixtures thereof.
Item 28. Item 27. The composition according to Item 26, wherein the active drug is selected from the group consisting of alendronate, olanzapine, risperidone, and ropinirole.
Item 29. Item 29. The composition according to any one of Items 1 to 28, comprising at least two groups of coated particles comprising different active drugs.
Item 30. Item 30. The composition according to any one of Items 1 to 29, further comprising an active drug or a pharmaceutically acceptable salt or solvate thereof on the outside of the coated particle.
Item 31. Any of paragraphs 1-30 comprising levodopa and carbidopa or benserazide in a ratio of 20: 1 to 1: 1, preferably 15: 1 to 2: 1, and most preferably 10: 1 to 4: 1. The composition according to item.
Item 32. The coated particles are based on the total weight of the coated particles,
(a) 1-50% by weight, especially 5-40% by weight, preferably 10-20% by weight of the at least one active drug;
(b) 1-50% by weight, especially 10-35% by weight, preferably 15-25% by weight of the ion exchange resin;
(c) 0-50% by weight, especially 1-50% by weight, preferably 10-40% by weight, more preferably 15-30% by weight of the release-modifying substance;
(d) 0.5-30% by weight of the bioadhesive substance, especially 1-10% by weight, preferably 2-8% by weight; and
(e) Any one of Items 1-31 containing 0 to 80% by weight, especially 1 to 80% by weight, preferably 10 to 60% by weight, more preferably 30 to 50% by weight of the enteric coating substance The composition according to item.
Item 33. (i) contacting the active drug with an ion exchange resin to obtain an active drug / ion exchange resin complex;
(ii) optionally, coating the composite of step (i) with a coating layer containing a release modifying substance;
(iii) coating the composite of step (i) or the coated composite of step (ii) with a coating layer containing a bioadhesive material; and
(iv) The method for producing a composition according to any one of items 1 to 32, further comprising a step of coating the coated composite of step (iii) with a coating layer containing an enteric coating substance. .

Claims (33)

  An oral pharmaceutical composition comprising coated particles of a complex of at least one active drug and an ion exchange resin, wherein the particles are coated with a bioadhesive coating layer containing at least one bioadhesive substance The oral pharmaceutical composition.   The composition of claim 1, wherein the coated particle further comprises an enteric coating layer positioned to cover the bioadhesive layer and containing at least one enteric coating material.   The composition of claim 2, wherein at least a portion of the coated particles further comprises a modified release coating layer located between the composite and the bioadhesive layer and containing at least one release modifying material. .   The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. 4. The composition of claim 3, selected from the group consisting of synthetic and modified polycarboxylate polymers that are by weight. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. 5. A composition according to claim 3 or 4.   The composition according to any one of claims 2 to 5, wherein the enteric coating substance is selected from the group consisting of an anionic cellulose derivative, an anionic vinyl resin and an anionic acrylic resin.   The enteric coating substance is cellulose acetate phthalate, cellulose diacetate, cellulose triacetate, methyl phthalate, hydroxypropyl cellulose, hydroxypropyl methyl phthalate, cellulose hexahydrophthalate, hexahydrophthalate Hydroxypropylmethylcellulose acid and their pharmaceutically acceptable salts, selected from the group consisting of polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate), and poly (methacrylic acid-co-methyl methacrylate) The composition according to claim 6.   The composition of claim 2, wherein the enteric coating layer is positioned to directly cover the bioadhesive layer.   The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. 9. The composition of claim 8, selected from the group consisting of synthetic and unmodified synthetic polycarboxylate polymers that are by weight. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. A composition according to claim 8 or 9.   The composition according to any one of claims 8 to 10, wherein the enteric coating substance is selected from the group consisting of an anionic cellulose derivative, an anionic vinyl resin and an anionic acrylic resin.   The enteric coating substance is cellulose acetate phthalate, cellulose diacetate, cellulose triacetate, methyl phthalate, hydroxypropyl cellulose, hydroxypropyl methyl phthalate, cellulose hexahydrophthalate, hexahydrophthalate Hydroxypropylmethylcellulose acid and their pharmaceutically acceptable salts, selected from the group consisting of polyvinyl acetate phthalate, poly (methacrylic acid-co-ethyl acrylate), and poly (methacrylic acid-co-methyl methacrylate) The composition of claim 11.   The composition of claim 1, wherein at least a portion of the coated particles further comprises a release modifying coating layer located between the composite and the bioadhesive layer and containing at least one release modifying material. .   The bioadhesive material has an average molecular weight of at least about 10,000 daltons, preferably at least about 50,000 daltons, more preferably at least about 100,000 daltons, even more preferably at least about 1,000,000 daltons, and most preferably from about 1,000,000 to about 10,000,000 daltons. 14. The composition of claim 13, selected from the group consisting of synthetic and unmodified synthetic polycarboxylate polymers that are by weight. The bioadhesive material is selected from the group consisting of suitably cross-linked homopolymers of acrylic acid or alkyl acrylic acid, and appropriately cross-linked copolymers of acrylic acid or methacrylic acid and acrylic acid (C ₁₀ -C ₃₀ ) alkyl. The composition according to claim 13 or 14.   16. A composition according to any one of claims 3-7 and 13-15, wherein the release modifying substance is selected from delayed release substances or sustained release substances.   The release-modifying substance is ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, poly (methacrylic acid-co-acrylic acid) Ethyl), poly (methacrylic acid-co-methyl methacrylate), polyvinyl chloride, polyvinyl acetate phthalate, poly (vinyl pyrrolidone-co-vinyl acetate), silicone elastomer, shellac, zein, rosin ester, and mixtures thereof The composition of claim 16, wherein the composition is selected from the group consisting of:   18. The composition of claim 17, wherein the release modifying material is selected from the group consisting of methylcellulose, ethylcellulose, and mixtures thereof.   19. A composition according to any one of the preceding claims, comprising at least two groups of coated particles differing in the amount and / or composition of the release modifying substance.   The ion exchange resin comprises polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups, and silica gel modified with ionic groups 20. A composition according to any one of the preceding claims, selected from the group, wherein the ionic group is selected from sulfonic acid groups, tertiary amine groups or quaternary ammonium groups.   21. The composition of claim 20, wherein the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinylbenzene.   The average particle size of the particles of the active drug and ion exchange resin complex is preferably from about 10 to about 3000 μm, especially from about 30 to about 2000 μm, and most preferably from about 50 to about 1000 μm. The composition according to any one of claims 1 to 21.   23. The average particle size of the coated particles is preferably from about 20 to about 5000 μm, especially from about 50 to about 4000 μm, and most preferably from about 70 to about 3000 μm. A composition according to 1.   24. A composition according to any one of claims 1 to 23, wherein the coated particles have a specific gravity in the range of 1.1 to 2.0, preferably 1.2 to 1.8. 25. A composition according to any one of the preceding claims, wherein the coated particles exhibit a specific surface area in the range of about 1 to 200 m < ² > / g.   The active drug is ondansetron, granisetron, tropisetron, dolasetron, palonosetron, aprepitant, sulfasalazine, doxazosin, atenolol, bisoprolol, hydrochlorothiazide, carvedilol, amlodipine, felodipine, nifedipine, verapamil, diltiazem, enalapril, prilapril, prilapril, prilapril Cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, fenofibrate, cholestyramine, oxybutynin, propiverine, solifenacin, trospium, darifenacin, sildenatamlo Teride, cyclophosphamide, chlorambucil, melphalan, busulfan, lomustine, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, capecitabine, vinblastine, vincristine, vindecine, cidetaxel , Actinomycin D, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, cisplatin, carboplatin, oxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, soratibib Amsacrine, Sparaginase, hydroxyurea, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, megestrol, tamoxifen, flutamide, nilutamide, bicalutamide, anastrozole, letrozole, exemestane, mycophenolate mofetil, sirolimus , Cyclosporine, tacrolimus, azathioprine, etidronic acid, clodronic acid, pamidronic acid, alendronic acid, tiludronic acid, ibandronic acid, risedronic acid, zoledronic acid, morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprenorphine, tramadol, acetylsalicylic acid , Metamizole, paracetamol, sumatriptan, methylphenobarbital , Phenobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, tiagabine, sultiam, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, phenethride, penezatum , Lacosamide, bechramid, trihexyphenidyl, biperidene, levodopa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocryptin, ropinirole, pramipexole, cabergoline, apomorphine, piribezil, rotigolasine, rotigolasine, rotigothine , Bulgepine, levomepromazine, Lupromazine, promazine, fluphenazine, perazine, haloperidol, sertindol, ziprasidone, zuclopentixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium, protipendil, risperidone, clothiapine, mosapramine, zotepine, aripiprazole, paliperidone , Diazepam, alprazolam, meprobamate, flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaprocrate, fluvoxamine, etoperidone, escitalopramil, escitalopramil Neostigmine, pyri Stigmine, disulfiram, naloxone, methadone, riluzole, abacavir, acyclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, troimipritol, glucose Ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorhradiol, hydrocodone, hydrocodone , 26. The composition according to any one of claims 1 to 25, selected from the group consisting of phenylpropanolamine, pseudoephedrine, and mixtures thereof.   27. The composition of claim 26, wherein the active drug is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone, and mixtures thereof.   27. The composition of claim 26, wherein the active drug is selected from the group consisting of alendronate, olanzapine, risperidone and ropinirole.   29. A composition according to any one of the preceding claims comprising at least two groups of coated particles comprising different active drugs.   30. The composition according to any one of claims 1 to 29, further comprising an active drug or a pharmaceutically acceptable salt or solvate thereof on the outside of the coated particles.   31. Any one of claims 1 to 30 comprising levodopa and carbidopa or benserazide in a ratio of 20: 1 to 1: 1, preferably 15: 1 to 2: 1, and most preferably 10: 1 to 4: 1. The composition according to one item. The coated particles are based on the total weight of the coated particles,
(a) 1-50% by weight, especially 5-40% by weight, preferably 10-20% by weight of the at least one active drug;
(b) 1-50% by weight, especially 10-35% by weight, preferably 15-25% by weight of the ion exchange resin;
(c) 0-50% by weight, especially 1-50% by weight, preferably 10-40% by weight, more preferably 15-30% by weight of the release-modifying substance;
(d) 0.5-30% by weight of the bioadhesive substance, especially 1-10% by weight, preferably 2-8% by weight; and
32. Any one of claims 1-31, comprising (e) 0-80% by weight, especially 1-80% by weight, preferably 10-60% by weight, more preferably 30-50% by weight of the enteric coating substance. The composition according to one item. (i) contacting the active drug with an ion exchange resin to obtain an active drug / ion exchange resin complex;
(ii) optionally, coating the composite of step (i) with a coating layer containing a release modifying substance;
(iii) coating the composite of step (i) or the coated composite of step (ii) with a coating layer containing a bioadhesive material; and
The production of the composition according to any one of claims 1 to 32, further comprising (iv) optionally coating the coated composite of step (iii) with a coating layer containing an enteric coating substance. Method.

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